Background of the Invention
[0001] The present invention relates to a process for preparing cyclic thioamides useful
for preparing aralkyl and aralkylidene heterocyclic lactams and imides, which are
selective agonists and antagonists of serotonin 1 (5-HT
1) receptors, specifically, of one or both of the 5-HT
1A and 5-HT
1D receptors, useful in treating or preventing migraine, depression and other disorders
for which a 5-HT
1 agonist or antagonist is indicated.
[0002] European Patent Publication 434,561, published on June 26, 1991, refers to 7-alkyl,
alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The
compounds are referred to as 5-HT
1 agonists and antagonists useful for the treatment of migraine, depression, anxiety,
schizophrenia, stress and pain.
[0003] European Patent Publication 343,050, published on November 23, 1989, refers to 7-unsubstituted,
halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes
as useful 5-HT
1A ligand therapeutics.
[0004] PCT publication WO 94/21619, published September 29, 1994, refers to naphthalene
derivatives as 5-HT
1 agonists and antagonists.
[0005] PCT publication WO 96/00720, published January 11, 1996, refers to naphthyl ethers
as useful 5-HT
1 agonists and antagonists.
[0006] European Patent Publication 701,819, published March 20, 1996, refers to the use
of 5-HT
1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
[0007] Glennon
et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT
1 ligand in their article "5-HT
1D Serotonin Receptors",
Clinical Drug Res. Dev.,
22, 25-36 (1991).
[0008] Glennon's article "Serotonin Receptors: Clinical Implications",
Neuroscience and Behavioral Reviews,
14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors
including appetite suppression, thermoregulation, cardiovascular/hypotensive effects,
sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's
disease and Huntington's disease.
[0009] World Patent Application WO 95/31988, published November 30, 1995, refers to the
use of a 5-HT
1D antagonist in combination with a 5-HT
1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic
disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic
stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's
disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm
(particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal
tract where changes in motility and secretion are involved, as well as sexual dysfunction.
[0010] G. Maura
et al.,
J. Neurochem,
66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT
1A receptors or for both 5-HT
1A and 5-HT
1D receptors might represent a great improvement in the treatment of human cerebellar
ataxias, a multifaceted syndrome for which no established therapy is available.
[0011] European Patent Publication 666,261, published August 9, 1995 refers to thiazine
and thiomorpholine derivatives which are claimed to be useful for the treatment of
cataracts.
Summary of the Invention
[0012] The present invention relates to a process for preparing a compound of the formula

wherein b is 0, 1, 2 or 3; Y is oxygen, sulfur, NH or N-acetyl; and each R
3 is independently selected from the group consisting of halo, cyano, (C
1-C
6)alkyl, (C
1-C
6)alkoxy and trifluoromethyl; comprising reacting a compound of the formula

with a dehydrating agent.
[0013] The present invention also relates to a more preferred process for preparing the
compound of formula I, wherein the dehydrating agent is acetic anhydride.
[0014] The present invention also relates to a process for preparing a compound of the formula

comprising reacting a compound of the formula

with haloacetic acid in the presence of a base.
[0015] The present invention also relates to a more preferred process for preparing the
compound of formula II, wherein the haloacetic acid is bromoacetic acid.
[0016] The present invention also relates to a more preferred process for preparing the
compound of formula II, wherein the base is potassium hydroxide.
[0017] The present invention also relates to a process for preparing a compound of the formula

comprising reacting a compound of the formula

with a reducing agent and reacting the compound so formed with hydrochloric acid.
[0018] The present invention also relates to a more preferred process for preparing the
compound of formula III, wherein the reducing agent is borane tetrahydrofuran complex.
[0019] The present invention also relates to a process for preparing a compound of the formula

comprising reacting a compound of the formula

with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid.
[0020] The present invention also relates to a more preferred process for preparing the
compound of formula IV, wherein the compoud of formula V is reacted with mercaptoacetic
acid.
[0021] The present invention also relates to a process for preparing a compound of the formula

wherein b is 0, 1, 2 or 3; Y is oxygen, sulfur, NH or N-acetyl; and each R
3 is independently selected from the group consisting of halo, cyano, (C
1-C
6)alkyl, (C
1-C
6)alkoxy and trifluoromethyl; comprising (a) reacting a compound of the formula

with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid;
(b) reacting a compound of formula IV so formed

with a reducing agent and reacting the intermediate compound so formed with hydrochloric
acid;
(c) reacting a compound of formula III so formed

with haloacetic acid in the presence of a base; and
(d) reacting a compound of formula II so formed

with a dehydrating agent.
[0022] The present invention also relates to a more preferred process for preparing the
compound of formula I, wherein the compound of formula V is reacted with mercaptoacetic
acid; the reducing agent is borane tetrahydrofuran complex; the base is potassium
hydroxide; the haloacetic acid is bromoacetic acid; and the dehydrating agent is acetic
anhydride.
[0023] The present invention also relates to a compound of the formula

[0024] The present invention also relates to a compound of the formula

[0025] The present invention also relates to a compound of the formula

Detailed Description of the Invention
[0026] The following reaction Schemes illustrate the preparation of the compounds of the
present invention. Unless otherwise indicated b, Y and R
3 in the reaction Schemes and the discussion that follow are defined as above.

[0027] In reaction 1 of Scheme 1, the aniline compound of formula
V is converted to the corresponding compound of formula
IV, wherein Y is oxygen, sulfur, NH or N-acetyl, by reacting
V with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid, in the presence
of an aprotic solvent, such as toluene. The reaction mixture so formed is heated to
reflux for a time period between 16 hours to about 24 hours, preferably about 20 hours.
[0028] In reaction 2 of Scheme
1, the compound of formula
IV is converted to the corresponding compound of formula
III by reducing
IV with a reducing agent, such as borane tetrahydrofuran complex. The compound so formed
is then treated with anhydrous hydrochloric acid in the presence of a polar protic
solvent, such as ethanol. The reaction is carried out at a temperature between about
10 °C to about 20 °C, preferably about 15 °C, for a time period between about 2 hours
to about 4 hours, preferably about 3 hours.
[0029] In reaction 3 of Scheme
1, the compound of formula
III is converted to the corresponding compound of formula
II by first treating
III with a base, such as potassium hydroxide, under inert atmosphere, in the presence
of a polar protic solvent, such as ethanol, at a temperature between about 0 °C to
about 20 °C, preferably about 10 °C, for a time period between about 0.5 hours to
about 2 hours, preferably about 1 hour. Alkylation of the intermediate compound so
formed is carried out with the addition of bromoacetic acid. The reaction mixture
is then stirred for an additional time period between about 2 hours to about 4 hours,
preferably about 3 hours.
[0030] In reaction 4 of Scheme
1, the compound of formula
II is converted to the corresponding compound of formula
I by reacting
II with excess acetic anhydride. The reaction mixture so formed is heated to reflux
for a time period between about 0.5 hours to about 2 hours, preferably about 1 hour.
[0031] In reaction 1 of Scheme
2, the compound of formula
VIII, wherein Q is a suitable leaving group, such as halo, preferably fluoro; X is hydrogen,
chloro, fluoro, bromo, iodo, cyano, (C
1-C
6)alkyl, hydroxy, trifluoromethyl, (C
1-C
6)alkoxy, -SO
t(C
1-C
6)alkyl wherein t is zero, one or two, -CO
2R
8 or -CONR
9R
10; wherein R
8 , R
9 and R
10 are each independently selected from hydrogen, (C
1-C
4)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted
with one or more substituents independently selected from chloro, fluoro, bromo, iodo,
(C
1-C
6)alkyl, (C
1-C
6)alkoxy, trifluoromethyl, cyano and -SO
k(C
1-C
6)alkyl wherein k is zero, one or two; and R
2 is hydrogen, (C
1-C
4)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted
with one or more substituents independently selected from chloro, fluoro, bromo, iodo,
(C
1-C
6)alkyl, (C
1-C
6)alkoxy, trifluoromethyl, cyano and -SO
k(C
1-C
6)alkyl wherein k is zero, one or two; is converted to the corresponding compound of
formula
VII, wherein R
1 is a group of the formula G
1, G
2, G
3, G
4, G
5 or G
6 depicted below,

a is zero to tour; p is 1, 2 or 3; R
4 is selected from the group consisting of hydrogen, (C
1-C
6)alkyl optionally substituted with (C
1-C
6)alkoxy or one to three fluorine atoms, or [(C
1-C
4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH
2)
q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl,
pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q
is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may
optionally be substituted with one or more substituents independently selected from
the group consisting of chloro, fluoro, bromo, iodo, (C
1-C
6)alkyl, (C
1-C
6)alkoxy, trifluoromethyl, cyano and -SO
9(C
1-C
6)alkyl, wherein g is zero, one or two; R
5 is selected from the group consisting of hydrogen, (C
1-C
6)alkyl, [(C
1-C
4)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH
2)
r-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl,
pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r
is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may
optionally be substituted with one or more substituents independently selected from
the group consisting of chloro, fluoro, bromo, iodo, (C
1-C
6)alkyl, (C
1-C
6)alkoxy, trifluoromethyl, -C(=O)-(C
1-C
6)alkyl, cyano and -SO
j(C
1-C
6)alkyl, wherein j is zero, one or two; or R
4 and R
5 taken together form a 2 to 4 carbon chain; R
6 is hydrogen or (C
1-C
6)alkyl; each R
7 is, independently, (C
1-C
4)alkyl or a (C
1-C
4)methylene bridge from one of the ring carbons of the piperazine ring of G
1 to the same or another ring carbon or a ring nitrogen of the piperazine ring of G
1 having an available bonding site, or to a carbon of R
4 having an available bonding site; and E, of formula G
3, is oxygen, sulfur, SO or SO
2; by reacting
VIII with a compound of the formula R
1H, wherein H refers to a hydrogen atom on group E from G
3 or nitrogen atoms from G
1, G
2, G
4, G
5 or G
6 and R
1 is defined as above, in the presence of base. This reaction is generally carried
out at a temperature from about 25°C to about 140°C, preferably at about the reflux
temperature, in a polar aprotic solvent, such as dimethyl sulfoxide, N,N-dimethylformamide,
N,N-dimethylacetamide or N-methyl-2-pyrrolidinone, preferably N-methyl-2-pyrrolidinone.
Suitable bases include anhydrous sodium carbonate, potassium carbonate, sodium hydroxide
and potassium hydroxide, as well as amines such as pyrrolidine, triethylamine and
pyridine. Anhydrous potassium carbonate is preferred.
[0032] In reaction 2 of Scheme
2, the compound of formula
VII is converted to the corresponding compound of formula
VI by subjecting
VII to an Aldol condensation-elimination. In an Aldol condensation, the compound of the
formula
VII is reacted with a compound of the formula
I

in the presence of a base, to form an Aldol intermediate of the formula
IX

which may be isolated or, preferably, converted directly in the same reaction step
to a compound of the formula
VI by the loss of water. The degree of completion for the conversion of compounds of
the formula
IX to the aldol product of formula
VI may be assessed using one or more analytical techniques, such as thin layer chromatography
(tlc) or high pressure liquid chromatography (hplc). In some instances it may be possible
or desirable to isolate the intermediate of formula
IX. In such case, the compound of formula
IX may be converted into the compound of formula
VI by the elimination of water using techniques which are familiar to those skilled
in the art, for example, by heating to the reflux temperature a solution of the compound
of formula
IX in a solvent such as benzene, toluene or xylene, in the presence of a catalytic amount
of benzene- or p-toluene-sulfonic acid with provision for the removal of the water
generated. Such water removal techniques may involve the use of molecular sieves or
a Dean-Stark trap to isolate the water created as an azeotrope with the solvent.
[0033] The Aldol reaction is typically carried out in an ether solvent such as methyl t-butyl
ether, isopropyl ether or tetrahydrofuran, at a temperature from about -78°C to about
25°C. Preferably, this reaction is carried out in tetrahydrofuran at about 25°C. Suitable
bases for use in the aldol formation step include sodium hydride, potassium-tert-butoxide,
lithium diisopropylamide, sodium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide.
Sodium bis(trimethyl-silyl)amide is preferred. Aldol condensations are described in
"
Modern Synthetic Reactions," Herbert O. House, 2d. Edition, W.A. Benjamin, Menlo Park, California, 629-682 (1972)
and
Tetrahedron,
38(20), 3059 (1982).
[0034] The compounds of the formula
VI which are basic in nature are capable of forming a wide variety of different salts
with various inorganic and organic acids. Although such salts must be pharmaceutically
acceptable for administration to animals, it is often desirable in practice to initially
isolate a compound of the formula
VI from the reaction mixture as a pharmaceutically unacceptable salt and then simply
convert the latter back to the free base compound by treatment with an alkaline reagent,
and subsequently convert the free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of formula
VI are readily prepared by treating the base compound with a substantially equivalent
amount of the chosen mineral or organic acid in an aqueous solvent medium or in a
suitable organic solvent such as methanol or ethanol. Upon careful evaporation of
the solvent, the desired solid salt is obtained.
[0035] The compounds of the formula
VI and its pharmaceutically acceptable salts (hereinafter also referred to as "the active
compound") are useful psychotherapeutics and are potent agonists and/or antagonists
of the serotonin 1A (5-HT
1A) and/or serotonin 1 (5-HT
1D) receptors. The active compound is useful in the treatment of hypertension, depression,
generalized anxiety disorder, phobias (
e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant
personality disorder, sexual dysfunction (
e.g., premature ejaculation), eating disorders (
e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (
e.g., addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and benzodiazepines),
cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,
panic disorder, memory disorders (
e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's
diseases (
e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias),
endocrine disorders (
e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar
ataxia, gastrointestinal tract disorders (involving changes in motility and secretion),
negative symptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome,
stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence,
cancer (
e.g. small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated
with vascular disorders).
[0036] The affinities of the compound of formula
VI for the various serotonin-1 receptors can be determined using standard radioligand
binding assays as described in the literature. The 5-HT
1A affinity can be measured using the procedure of Hoyer
et al. (
Brain Res.,
376, 85 (1986)). The 5-HT
1D affinity can be measured using the procedure of Heuring and Peroutka (
J. Neurosci.,
7, 894 (1987)).
[0037] The
in vitro activity of the compound of formula
VI at the 5-HT
1D binding site may be determined according to the following procedure. Bovine caudate
tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS·hydrochloride
(tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. The homogenate is
then centrifuged at 45,000G for 10 minutes. The supernatant is then discarded and
the resulting pellet resuspended in approximately 20 volumes of 50 mM TRIS·hydrochloride
buffer at pH 7.7. This suspension is then pre-incubated for 15 minutes at 37°C, after
which the suspension is centrifuged again at 45,000G for 10 minutes and the supernatant
discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of
a buffer of 15 mM TRIS·hydrochloride containing 0.01 percent ascorbic acid with a
final pH of 7.7 and also containing 10 µM pargyline and 4 mM calcium chloride (CaCl
2). The suspension is kept on ice at least 30 minutes prior to use.
[0038] The inhibitor, control or vehicle is then incubated according to the following procedure.
To 50 µl of a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution
is added 200 µl of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS·hydrochloride
containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 µM pargyline
and 4 µM calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline)
and 100 nM of mesulergine. To this mixture is added 750 µl of bovine caudate tissue,
and the resulting suspension is vortexed to ensure a homogenous suspension. The suspension
is then incubated in a shaking water bath for 30 minutes at 25°C. After incubation
is complete, the suspension is filtered using glass fiber filters (
e.g., Whatman GF/B-filters™). The pellet is then washed three times with 4 ml of a buffer
of 50 mM TRIS·hydrochloride at pH 7.7. The pellet is then placed in a scintillation
vial with 5 ml of scintillation fluid (aquasol 2 ™) and allowed to sit overnight.
The percent inhibition can be calculated for each dose of the compound. An IC
50 value can then be calculated from the percent inhibition values.
[0039] The activity of the compound of formula
VI for 5-HT
1A binding ability can be determined according to the following procedure. Rat brain
cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with
10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900G
for 10 minutes and the supernate separated and recentrifuged at 70,000G for 15 minutes.
The supernate is discarded and the pellet resuspended in 10 volumes of 15 mM TRIS·hydrochloride
at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37°C. After pre-incubation
is complete, the suspension is centrifuged at 70,000G for 15 minutes and the supernate
discarded. The resulting tissue pellet is resuspended in a buffer of 50 mM TRIS·hydrochloride
at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid. The
tissue is stored at -70°C until ready for an experiment. The tissue can be thawed
immediately prior to use, diluted with 10 µm pargyline and kept on ice.
[0040] The tissue is then incubated according to the following procedure. Fifty microliters
of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared
at various dosages. To this solution is added 200µl of tritiated DPAT at a concentration
of 1.5 nM in a buffer of 50 mM TRIS·hydrochloride at pH 7.7 containing 4 mM calcium
chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added
750 µl of tissue and the resulting suspension is vortexed to ensure homogeneity. The
suspension is then incubated in a shaking water bath for 30 minutes at 37°C. The solution
is then filtered, washed twice with 4 ml of 10 mM TRIS·hydrochloride at pH 7.5 containing
154 mM of sodium chloride. The percent inhibition is calculated for each dose of the
compound, control or vehicle. IC
50 values are calculated from the percent inhibition values.
[0041] The agonist and antagonist activities of the compound of formula
VI at 5-HT
1A and 5-HT
1D receptors can be determined using a single saturating concentration according to
the following procedure. Male Hartley guinea pigs are decapitated and 5-HT
1A receptors are dissected out of the hippocampus, while 5-HT
1D receptors are obtained by slicing at 350 mM on a Mcllwain tissue chopper and dissecting
out the substantia nigra from the appropriate slices. The individual tissues are homogenized
in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon®
homogenizer and centrifuged at 35,000 x g for 10 minutes at 4°C. The pellets are resuspended
in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration
of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube. The following
agents are added so that the reaction mix in each tube contained 2.0 mM MgCl
2, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine
phosphokinase, 100 µM GTP and 0.5-1 microcuries of [
32P]-ATP (30 Ci/mmol: NEG-003 - New England Nuclear). Incubation is initiated by the
addition of tissue to siliconized microfuge tubes (in triplicate) at 30°C for 15 minutes.
Each tube receives 20 µL tissue, 10 µL drug or buffer (at 10X final concentration),
10µL 32 nM agonist or buffer (at 10X final concentration), 20µL forskolin (3 µM final
concentration) and 40 µL of the preceding reaction mix. Incubation is terminated by
the addition of 100 µL 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm
[
3H]-cAMP (30 Ci/mmol: NET-275 - New England Nuclear) to monitor the recovery of cAMP
from the columns. The separation of [
32P]-ATP and [
32P]-cAMP is accomplished using the method of Salomon
et al.,
Analytical Biochemistry,
1974,
58, 541-548. Radioactivity is quantified by liquid scintillation counting. Maximal inhibition
is defined by 10 µM (R)-8-OH-DPAT for 5-HT
1A receptors, and 320 nM 5-HT for 5-HT
1D receptors. Percent inhibitions by the test compounds are then calculated in relation
to the inhibitory effect of (R)-8-OH-DPAT for 5-HT
1A receptors or 5-HT for 5-HT
1D receptors. The reversal of agonist induced inhibition of forskolin-stimulated adenylate
cyclase activity is calculated in relation to the 32 nM agonist effect.
[0042] The compound of formula
VI can be tested for
in vivo activity for antagonism of 5-HT
1D agonist-induced hypothermia in guinea pigs according to the following procedure.
[0043] Male Hartley guinea pigs from Charles River, weighing 250-275 grams on arrival and
300-600 grams at testing, serve as subjects in the experiment. The guinea pigs are
housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule
for at least seven days prior to experimentation. Food and water are available
ad libitum until the time of testing.
[0044] The compound of formula
VI can be administered as solution in a volume of 1 ml/kg. The vehicle used is varied
depending on compound solubility. Test compounds are typically administered either
sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT
1D agonist, such as [3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine,
which can be prepared as described in PCT publication WO93/11106, published June 10,
1993 which is administered at a dose of 5.6 mg/kg, s.c. Before a first temperature
reading is taken, each guinea pig is placed in a clear plastic shoe box containing
wood chips and a metal grid floor and allowed to acclimate to the surroundings for
30 minutes. Animals are then returned to the same shoe box after each temperature
reading. Prior to each temperature measurement each animal is firmly held with one
hand for a 30-second period. A digital thermometer with a small animal probe is used
for temperature measurements. The probe is made of semi-flexible nylon with an epoxy
tip. The temperature probe is inserted 6 cm into the rectum and held there for 30
seconds or until a stable recording is obtained. Temperatures are then recorded.
[0045] In p.o. screening experiments, a "pre-drug" baseline temperature reading is made
at -90 minutes, the test compound is given at -60 minutes and an additional -30 minute
reading is taken. The 5-HT
1D agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120
and 240 minutes later.
[0046] In subcutaneous screening experiments, a pre-drug baseline temperature reading is
made at -30 minutes. The test compound and 5-HT
1D agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240
minutes later.
[0047] Data are analyzed with two-way analysis of variants with repeated measures in Newman-Keuls
post hoc analysis.
[0048] The active compound of formula
VI can be evaluated as anti-migraine agents by testing the extent to which they mimic
sumatriptan in contracting the dog isolated saphenous vein strip [P.P.A. Humphrey
et al.,
Br. J. Pharmacol.,
94, 1128 (1988)]. This effect can be blocked by methiothepin, a known serotonin antagonist.
Sumatriptan is known to be useful in the treatment of migraine and produces a selective
increase in carotid vascular resistance in the anesthetized dog. The pharmacological
basis of sumatriptan efficacy has been discussed in W. Fenwick
et al.,
Br. J. Pharmacol.,
96, 83 (1989).
[0049] The serotonin 5-HT
1 agonist activity can be determined by the
in vitro receptor binding assays, as described for the 5-HT
1A receptor using rat cortex as the receptor source and [
3H]-8-OH-DPAT as the radioligand [D. Hoyer et al.
Eur. J. Pharm.,
118, 13 (1985)] and as described for the 5-HT
1D receptor using bovine caudate as the receptor source and [
3H]serotonin as the radioligand [R.E. Heuring and S.J. Peroutka,
J. Neuroscience,
7, 894 (1987)].
[0050] The compound of formula
VI may advantageously be used in conjunction with one or more other therapeutic agents,
for instance, different antidepressant agents such as tricyclic antidepressants (
e.g., amitriptyline, dothiepin, doxepin, trimipramine, butripyline, clomipramine, desipramine,
imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase
inhibitors (
e.g., isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptake inhibitors (
e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), and/or with antiparkinsonian
agents such as dopaminergic antiparkinsonian agents (
e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor
e.g., benserazide or carbidopa, or with a dopamine agonist
e.g., bromocriptine, lysuride or pergolide).
[0051] The compound of the formula
VI and the pharmaceutically acceptable salts thereof, in combination with a 5-HT re-uptake
inhibitor (
e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), preferably sertraline, or a
pharmaceutically acceptable salt or polymorph thereof (the combination of a compound
of formula
VI with a 5-HT re-uptake inhibitor is referred to herein as "the active combination"),
are useful psychotherapeutics and may be used in the treatment or prevention of disorders
the treatment or prevention of which is facilitated by enhanced serotonergic neurotransmission
(
e.g., hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress
syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity,
chemical dependencies, cluster headache, migraine, pain. Alzheimer's disease, obsessive-compulsive
disorder, panic disorder, memory disorders (
e.g., dementia, amnestic disorders, and age-associated memory impairment), Parkinson's
diseases (
e.g., dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias),
endocrine disorders (
e.g., hyperprolactinaemia). vasospasm (particularly in the cerebral vasculature), cerebellar
ataxia, gastrointestinal tract disorders (involving changes in motility and secretion)
chronic paroxysmal hemicrania and headache (associated with vascular disorders).
[0052] Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibit positive activity
against depression; chemical dependencies; anxiety disorders including panic disorder,
generalized anxiety disorder, agoraphobia, simple phobias, social phobia, and post-traumatic
stress disorder; obsessive-compulsive disorder; avoidant personality disorder and
premature ejaculation in mammals, including humans, due in part to their ability to
block the synaptosomal uptake of serotonin.
[0053] United States Patent 4,536,518 describes the synthesis, pharmaceutical composition
and use of sertraline for depression and is hereby incorporated by reference in its
entirety. PCT publication WO98/14433 relates to novel aralkyl and aralkylidene heterocyclic
lactams and imides, to intermediates for their preparation, to pharmaceutical compositions
containing them and to their medicinal use and is hereby incorporated by reference
in its entirety.
[0054] Activity of the active combination as antidepressants and related pharmacological
properties can be determined by methods (1)-(4) below, which are described in Koe,
B.
et al.,
Journal of Pharmacology and Experimental Therapeutics,
226 (3), 686-700 (1983). Specifically, activity can be determined by studying (1) their
ability to affect the efforts of mice to escape from a swim-tank (Porsolt mouse "behavior
despair" test), (2) their ability to potentiate 5-hydroxytryptophan-induced behavioral
symptoms in mice in vivo, (3) their ability to antagonize the serotonin-depleting
activity of p-chloroamphetamine hydrochloride in rat brain
in vivo, and (4) their ability to block the uptake of serotonin, norepinephrine and dopamine
by synaptosomal rat brain cells
in vitro. The ability of the active combination to counteract reserpine hypothermia in mice
in vivo can be determined according to the methods described in U.S. Pat. No. 4,029,731.
[0055] The compositions of the compound of formula
VI may be formulated in a conventional manner using one or more pharmaceutically acceptable
carriers. Thus, the active compound of formula
VI may be formulated for oral, buccal, intranasal, parenteral (
e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form
suitable for administration by inhalation or insufflation.
[0056] For oral administration, the pharmaceutical compositions may take the form of, for
example, tablets or capsules prepared by conventional means with pharmaceutically
acceptable excipients such as binding agents (
e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose):
fillers (
e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (
e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium
starch glycolate); or wetting agents (
e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the
art. Liquid preparations for oral administration may take the form of, for example,
solutions, syrups or suspensions, or they may be presented as a dry product for constitution
with water or other suitable vehicle before use. Such liquid preparations may be prepared
by conventional means with pharmaceutically acceptable additives such as suspending
agents (
e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents
(
e.g., lecithin or acacia); non-aqueous vehicles (
e.g., almond oil, oily esters or ethyl alcohol); and preservatives (
e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
[0057] For buccal administration, the composition may take the form of tablets or lozenges
formulated in conventional manner.
[0058] The active compound of formula
VI may be formulated for parenteral administration by injection, including using conventional
catheterization techniques or infusion. Formulations for injection may be presented
in unit dosage form,
e.g., in ampules or in multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulating agents such as suspending, stabilizing and/or dispersing
agents. Alternatively, the active ingredient may be in powder form for reconstitution
with a suitable vehicle,
e.g., sterile pyrogen-free water, before use.
[0059] The active compound of formula
VI may also be formulated in rectal compositions such as suppositories or retention
enemas,
e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[0060] For intranasal administration or administration by inhalation, the active compound
of formula
VI are conveniently delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an aerosol spray presentation
from a pressurized container or a nebulizer, with the use of a suitable propellant,
e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon
dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit
may be determined by providing a valve to deliver a metered amount. The pressurized
container or nebulizer may contain a solution or suspension of the active compound.
Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or
insufflator may be formulated containing a powder mix of a compound of formula
VI and a suitable powder base such as lactose or starch.
[0061] A proposed dose of the active compound of formula
VI for oral, parenteral or buccal administration to the average adult human for the
treatment of the conditions referred to above (
e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could
be administered, for example, 1 to 4 times per day.
[0062] Aerosol formulations for treatment of the conditions referred to above (
e.g., migraine) in the average adult human are preferably arranged so that each metered
dose or "puff" of aerosol contains 20µg to 1000µg of the compound of formula
VI. The overall daily dose with an aerosol will be within the range 100µg to 10 mg.
Administration may be several times daily, for example 2, 3, 4 or 8 times, giving
for example, 1, 2 or 3 doses each time.
[0063] In connection with the use of an active compound of formula
VI with a 5-HT re-uptake inhibitor, preferably sertraline, for the treatment of subjects
possessing any of the above conditions, it is to be noted that these compounds may
be administered either alone or in combination with pharmaceutically acceptable carriers
by either of the routes previously indicated, and that such administration can be
carried out in both single and multiple dosages. More particularly, the active combination
can be administered in a wide variety of different dosage forms,
i.e., they may be combined with various pharmaceutically-acceptable inert carriers in
the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous
suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include
solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents,
etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or
flavored by means of various agents of the type commonly employed for such purposes.
In general, the compounds of formula I are present in such dosage forms at concentration
levels ranging from about 0.5% to about 90% by weight of the total composition, i.e.,
in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake
inhibitor, preferably sertraline, is present in such dosage forms at concentration
levels ranging from about 0.5% to about 90% by weight of the total composition,
i.e., in amounts which are sufficient to provide the desired unit dosage.
[0064] A proposed daily dose of an active compound of formula
VI in the combination formulation (a formulation containing an active compound of formula
VI and a 5-HT re-uptake inhibitor) for oral, parenteral, rectal or buccal administration
to the average adult human for the treatment of the conditions referred to above is
from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg
of the active ingredient of formula I per unit dose which could be administered, for
example, 1 to 4 times per day.
[0065] A proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the
combination formulation for oral, parenteral or buccal administration to the average
adult human for the treatment of the conditions referred to above is from about 0.1
mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake
inhibitor per unit dose which could be administered, for example, 1 to 4 times per
day.
[0066] A preferred dose ratio of sertraline to an active compound of formula
VI in the combination formulation for oral, parenteral or buccal administration to the
average adult human for the treatment of the conditions referred to above is from
about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
[0067] Aerosol combination formulations for treatment of the conditions referred to above
in the average adult human are preferably arranged so that each metered dose or "puff"
of aerosol contains from about 0.01 µg to about 100 mg of the active compound of formula
VI, preferably from about 1 µg to about 10 mg of such compound. Administration may be
several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3
doses each time.
[0068] Aerosol formulations for treatment of the conditions referred to above in the average
adult human are preferably arranged so that each metered dose or "puff" of aerosol
contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably
sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration
may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1,
2 or 3 doses each time.
[0069] As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination
with compounds of formula
VI are readily adapted to therapeutic use as antidepressant agents. In general, these
antidepressant compositions containing a 5-HT re-uptake inhibitor, preferably sertraline,
and a compound of formula
VI are normally administered in dosages ranging from about 0.01 mg to about 100 mg per
kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably
from about 0.1 mg to about 10 mg per kg of body weight per day of sertraline; with
from about 0.001 mg to about 100 mg per kg of body weight per day of a compound of
formula
VI, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a
compound of formula
VI, although variations will necessarily occur depending upon the conditions of the
subject being treated and the particular route of administration chosen.
[0070] The following Examples illustrate the preparation of the compounds of the present
invention. Melting points are uncorrected. NMR data are reported in parts per million
(8) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform
unless otherwise specified). Commercial reagents were utilized without further purification.
PREPARATION A
2-(3,4-Dichloro-phenylamino)-ethanethiol-hydrochloride
[0071] A 3-necked 2 L round bottomed flask equipped with an overhead stirrer, temperature
probe and reflux condenser with Dean-Stark trap was charged with 100.0 grams (0.617
mol) of 3,4-dichloroaniline and 500 mL of toluene. The resulting solution was then
treated with 64.4 mL (0.927 mol, 1.5 equivalents) of mercaptoacetic acid. The solution
was heated to reflux (130 °C ), while collecting water in the Dean-Stark trap for
20 hours, then cooled to room temperature. Ethyl acetate (250 mL) was then added followed
by 123 mL of 1N hydrochloric acid. The layers were separated and the organic layer
washed with 250 mL of water then 500 mL of saturated aqueous sodium bicarbonate and
concentrated under vacuum to a volume of approximately 200 mL. After addition of 200
mL of toluene, the solution was again concentrated to approximately 200 mL, diluted
with 1 L of tetrahydrofuran and filtered. This filtrate was added dropwise to a nitrogen-purged
3-necked 5 L round bottomed flask containing 1.73 L (1.73 mol, 2.80 equivalents) of
1N borane-tetrahydrofuran complex while maintaining a temperature of 10-15 °C. Some
gassing was observed. The reaction mixture was warmed to room temperature and stirred
overnight then cooled to 10 °C . A solution of 252 grams (6.91 mol, 11.2 equivalents)
of anhydrous hydrogen chloride in 840 mL of ethanol was added at 10-15 °C during which
time significant gas evolution was observed and solids precipitated. After stirring
for 1 hour at 5-10 °C the solids were collected by filtration, washed with tetrahydrofuran,
and dried under vacuum to yield 100.0 grams (62.6 % yield) of the title compound as
a white solid, mp 185-188 °C.
1H NMR (DMF-
d7) δ 7.20 (d,
J=8.7 Hz, 1H), 7.01 (d,
J=2.7 Hz, 1H), 6.78 (dd,
J=2.7, 8.7 Hz, 1H), 3.18 (dd,
J=6.4, 7.7 Hz, 2H) 2.61 (br s, 2H), 2.37 (br s, 1H).
13C NMR (DMF-
d7) δ 146.02, 132.94, 134.90, 122.70, 118.09, 117.19, 50.05, 23.07. HRMS (FAB) calcd
for C
8H
9Cl
2NS: 221.9911; found: 221.9893.
EXAMPLE 1
4-(3,4-Dichloro-phenyl)-thiomorpholin-3-one
[0072] A 3-necked 3 L round bottomed flask equipped with overhead stirrer, temperature probe,
and nitrogen inlet was charged with 100 grams (0.387 mol) of 2-(3,4-dichloro-phenylamino)-ethanethiol
hydrochloride and 1 L of 2B-ethanol. To the resulting suspension was charged 76 grams
(1.35 mol, 3.5 equivalents) of potassium hydroxide. The addition resulted in a temperature
increase to approximately 35 °C. This suspension was stirred at room temperature for
15-20 minutes, then cooled to 5-10 °C and treated with a solution of 59.1 grams (0.425
mol, 1.1 equivalents) of bromoacetic acid in 152 mL of 2B-ethanol. After stirring
at room temperature for approximately 3 hours, the reaction mixture was concentrated
under vacuum to a volume of approximately 225 mL. To this suspension was added 864
mL (9.15 mol, 23.6 equivalents) of acetic anhydride with no external cooling which
resulted in a temperature increase to approximately 100 °C. The flask was fitted with
a condenser and receiving flask, and heated to 105-110 °C at which point distillate
began to be collected. With continued heating, the internal temperature rose to 115
°C, the reaction flask was refitted with a reflux condenser and the reaction mixture
held at reflux for 1 hour. After allowing to cool to room temperature, the reaction
mixture was poured into a 3-necked 5 L round bottomed flask containing 1700 mL of
water and 864 mL of methylene chloride and stirred for 10-20 minutes at 20-25 °C.
The layers were separated and the organic layer was washed with 1 L of water then
treated with 2 L of 10% aqueous sodium hydroxide which brought the pH to 9-10. The
layers were separated, the organic layer was dried over magnesium sulfate, and concentrated
atmospherically to a volume of approximately 200 mL. Displacement of the methylene
chloride by isopropyl ether was accomplished by continuing to charge isopropyl ether
and concentrating until an internal temperature of 68 °C was attained. The solution
was then cooled to room temperature. Solids began to precipitate at 45 °C. The resulting
slurry was stirred at room temperature for two hours. The solids were collected by
filtration, washed with isopropyl ether and vacuum dried at 45-50 °C to yield 57.5
grams (56.7 % yield ) of the title compound as a white solid, mp 81-83 °C.
1H NMR (CDCl
3) δ 7.44 (d,
J=8.7 Hz, 1H), 7.38 (d,
J=2.5 Hz, 1H), 7.13 (d,
J=2.5 Hz, 1H), 3.93 (t,
J=11.5 Hz, 2H), 3.43 (s, 2H), 3.01 (t,
J=11.5 Hz, 2H).
13C NMR (CDCl
3) δ 168.10, 143.04, 134.201, 132.25, 132.09, 129.42, 126.83, 53.32, 31.81, 27.86.
HRMS (FAB) calcd for C
10H
9Cl
2NOS: 261.9860; found: 261.9839.